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Archives of Pharmacal Research Apr 2023Prenylated flavonoids are a special kind of flavonoid derivative possessing one or more prenyl groups in the parent nucleus of the flavonoid. The presence of the prenyl... (Review)
Review
Prenylated flavonoids are a special kind of flavonoid derivative possessing one or more prenyl groups in the parent nucleus of the flavonoid. The presence of the prenyl side chain enriched the structural diversity of flavonoids and increased their bioactivity and bioavailability. Prenylated flavonoids show a wide range of biological activities, such as anti-cancer, anti-inflammatory, neuroprotective, anti-diabetic, anti-obesity, cardioprotective effects, and anti-osteoclastogenic activities. In recent years, many compounds with significant activity have been discovered with the continuous excavation of the medicinal value of prenylated flavonoids, and have attracted the extensive attention of pharmacologists. This review summarizes recent progress on research into natural active prenylated flavonoids to promote new discoveries of their medicinal value.
Topics: Flavonoids; Prenylation
PubMed: 37055613
DOI: 10.1007/s12272-023-01443-4 -
Chemical & Pharmaceutical Bulletin 2023Teleocidins are natural products belonging to the indole alkaloid family and show potent protein kinase C activation activity. The structural feature of teleocidins is... (Review)
Review
Teleocidins are natural products belonging to the indole alkaloid family and show potent protein kinase C activation activity. The structural feature of teleocidins is an indole-fused nine-membered lactam ring structure. Due to their unique structures and strong biological activities, many total synthesis and biosynthetic studies of teleocidins have been performed. Teleocidin biosynthesis involves interesting enzymatic reactions that are challenging in organic synthesis, including oxidative intramolecular C-N bond-forming reactions, regio- and stereo-selective reverse prenylation reactions, and methylation-triggered terpene cyclization. This review summarizes the recent research on functional and structural analyses, as well as enzyme engineering, of teleocidin biosynthetic enzymes.
Topics: Cyclization; Lyngbya Toxins; Phosphorylation; Prenylation; Protein Kinase C
PubMed: 36858523
DOI: 10.1248/cpb.c22-00849 -
Cell Metabolism Dec 2020Effector regulatory T (eT) cells are essential for immune tolerance and depend upon T cell receptor (TCR) signals for generation. The immunometabolic signaling...
Effector regulatory T (eT) cells are essential for immune tolerance and depend upon T cell receptor (TCR) signals for generation. The immunometabolic signaling mechanisms that promote the differentiation and maintenance of eT cells remain unclear. Here, we show that isoprenoid-dependent posttranslational lipid modifications dictate eT cell accumulation and function by intersecting with TCR-induced intracellular signaling. We find that isoprenoids are essential for activated T cell suppressive activity, and T cell-specific deletion of the respective farnesylation- and geranylgeranylation-promoting enzymes Fntb or Pggt1b leads to the development of fatal autoimmunity, associated with reduced eT cell accumulation. Mechanistically, Fntb promotes eT cell maintenance by regulating mTORC1 activity and ICOS expression. In contrast, Pggt1b acts as a rheostat of TCR-dependent transcriptional programming and Rac-mediated signaling for establishment of eT cell differentiation and immune tolerance. Therefore, our results identify bidirectional metabolic signaling, specifically between immunoreceptor signaling and metabolism-mediated posttranslational lipid modifications, for the differentiation and maintenance of eT cells.
Topics: Animals; Cell Differentiation; Female; Immune Tolerance; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein Prenylation; T-Lymphocytes, Regulatory; Terpenes
PubMed: 33207246
DOI: 10.1016/j.cmet.2020.10.022 -
Current Opinion in Structural Biology Aug 2022The ubiquitous UbiX-UbiD system is associated with a wide range of microbial (de)carboxylation reactions. Recent X-ray crystallographic studies have contributed to... (Review)
Review
The ubiquitous UbiX-UbiD system is associated with a wide range of microbial (de)carboxylation reactions. Recent X-ray crystallographic studies have contributed to elucidating the enigmatic mechanism underpinning the conversion of α,β-unsaturated acids by this system. The UbiD component utilises a unique cofactor, prenylated flavin (prFMN), generated by the bespoke action of the associated UbiX flavin prenyltransferase. Structure determination of a range of UbiX/UbiD representatives has revealed a generic mode of action for both the flavin-to-prFMN metamorphosis and the (de)carboxylation. In contrast to the conserved UbiX, the UbiD superfamily is associated with a versatile substrate range. The latter is reflected in the considerable variety of UbiD quaternary structure, dynamic behaviour and active site architecture. Directed evolution of UbiD enzymes has taken advantage of this apparent malleability to generate new variants supporting in vivo hydrocarbon production. Other applications include coupling UbiD to carboxylic acid reductase to convert alkenes into α,β-unsaturated aldehydes via enzymatic CO fixation.
Topics: Aspergillus niger; Carboxy-Lyases; Decarboxylation; Flavins; Prenylation
PubMed: 35843126
DOI: 10.1016/j.sbi.2022.102432 -
Platelets Dec 2023Statins inhibit the mevalonate pathway by impairing protein prenylation via depletion of lipid geranylgeranyl diphosphate (GGPP). Rab27b and Rap1a are small GTPase...
Statins inhibit the mevalonate pathway by impairing protein prenylation via depletion of lipid geranylgeranyl diphosphate (GGPP). Rab27b and Rap1a are small GTPase proteins involved in dense granule secretion, platelet activation, and regulation. We analyzed the impact of statins on prenylation of Rab27b and Rap1a in platelets and the downstream effects on fibrin clot properties. Whole blood thromboelastography revealed that atorvastatin (ATV) delayed clot formation time ( < .005) and attenuated clot firmness ( < .005). ATV pre-treatment inhibited platelet aggregation and clot retraction. Binding of fibrinogen and P-selectin exposure on stimulated platelets was significantly lower following pre-treatment with ATV ( < .05). Confocal microscopy revealed that ATV significantly altered the structure of platelet-rich plasma clots, consistent with the reduced fibrinogen binding. ATV enhanced lysis of Chandler model thrombi 1.4-fold versus control ( < .05). Western blotting revealed that ATV induced a dose-dependent accumulation of unprenylated Rab27b and Rap1a in the platelet membrane. ATV dose-dependently inhibited ADP release from activated platelets. Exogenous GGPP rescued the prenylation of Rab27b and Rap1a, and partially restored the ADP release defect, suggesting these changes arise from reduced prenylation of Rab27b. These data demonstrate that statins attenuate platelet aggregation, degranulation, and binding of fibrinogen thereby having a significant impact on clot contraction and structure.
Topics: Humans; Adenosine Diphosphate; Atorvastatin; Blood Platelets; Fibrinogen; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Prenylation; rab GTP-Binding Proteins; rap1 GTP-Binding Proteins; Thrombosis
PubMed: 37139869
DOI: 10.1080/09537104.2023.2206921 -
Nature Communications Jun 2023Prenylated and reverse-prenylated indolines are privileged scaffolds in numerous naturally occurring indole alkaloids with a broad spectrum of important biological...
Prenylated and reverse-prenylated indolines are privileged scaffolds in numerous naturally occurring indole alkaloids with a broad spectrum of important biological properties. Development of straightforward and stereoselective methods to enable the synthesis of structurally diverse prenylated and reverse-prenylated indoline derivatives is highly desirable and challenging. In this context, the most direct approaches to achieve this goal generally rely on transition-metal-catalyzed dearomative allylic alkylation of electron-rich indoles. However, the electron-deficient indoles are much less explored, probably due to their diminished nucleophilicity. Herein, a photoredox-catalyzed tandem Giese radical addition/Ireland-Claisen rearrangement is disclosed. Diastereoselective dearomative prenylation and reverse-prenylation of electron-deficient indoles proceed smoothly under mild conditions. An array of tertiary α-silylamines as radical precursors is readily incorporated in 2,3-disubstituted indolines with high functional compatibility and excellent diastereoselectivity (>20:1 d.r.). The corresponding transformations of the secondary α-silylamines provide the biologically important lactam-fused indolines in one-pot synthesis. Subsequently, a plausible photoredox pathway is proposed based on control experiments. The preliminary bioactivity study reveals a potential anticancer property of these structurally appealing indolines.
Topics: Electrons; Prenylation; Alkylation; Antipsychotic Agents; Indoles; Catalysis
PubMed: 37391418
DOI: 10.1038/s41467-023-39633-9 -
The New Phytologist Jan 2015Membranes have long been known to act as more than physical barriers within and between plant cells. Trafficking of membrane proteins, signalling from and across... (Review)
Review
Membranes have long been known to act as more than physical barriers within and between plant cells. Trafficking of membrane proteins, signalling from and across membranes, organisation of membranes and transport through membranes are all essential processes for plant cellular function. These processes rely on a myriad array of proteins regulated in a variety of manners and are frequently required to be directly associated with membranes. For integral membrane proteins, the mode of membrane association is readily apparent, but many peripherally associated membrane proteins are outwardly soluble proteins. In these cases the proteins are frequently modified by the addition of lipids allowing direct interaction with the hydrophobic core of membranes. These modifications include N-myristoylation, S-acylation (palmitoylation), prenylation and GPI anchors but until recently little was truly known about their function in plants. New data suggest that these modifications are able to act as more than just membrane anchors, and dynamic S-acylation in particular is emerging as a means of regulating protein function in a similar manner to phosphorylation. This review discusses how these modifications occur, their impact on protein function, how they are regulated, recent advances in the field and technical approaches for studying these modifications.
Topics: Acylation; Lipid Metabolism; Lipoproteins; Membrane Microdomains; Membrane Proteins; Models, Biological; Plant Proteins; Plants; Prenylation; Protein Processing, Post-Translational; Protein Transport
PubMed: 25283240
DOI: 10.1111/nph.13085 -
International Journal of Molecular... Dec 2022Multiple myeloma (MM) is a plasma cell malignancy for which there is currently no cure. While treatment options for MM have expanded over the last two decades, all... (Review)
Review
Multiple myeloma (MM) is a plasma cell malignancy for which there is currently no cure. While treatment options for MM have expanded over the last two decades, all patients will eventually become resistant to current therapies. Thus, there is an urgent need for novel therapeutic strategies to treat MM. The isoprenoid biosynthetic pathway (IBP) is responsible for the post-translational modification of proteins belonging to the Ras small GTPase superfamily, such as Ras, Rho and Rab family members. Given the important roles these GTPase proteins play in various cellular processes, there is significant interest in the development of inhibitors that disturb their prenylation and consequently their activity in MM cells. Numerous preclinical studies have demonstrated that IBP inhibitors have anti-MM effects, including the induction of apoptosis in MM cells and inhibition of osteoclast activity. Some IBP inhibitors have made their way into the clinic. For instance, nitrogenous bisphosphonates are routinely prescribed for the management MM bone disease. Other IBP inhibitors, including statins and farnesyltransferase inhibitors, have been evaluated in clinical trials for MM, while there is substantial preclinical investigation into geranylgeranyl diphosphate synthase inhibitors. Here we discuss recent advances in the development of IBP inhibitors, assess their mechanism of action and evaluate their potential as anti-MM agents.
Topics: Humans; Multiple Myeloma; Biosynthetic Pathways; Diphosphonates; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Terpenes; Protein Prenylation
PubMed: 36613550
DOI: 10.3390/ijms24010111 -
The Journal of Biological Chemistry Jun 2023Identifying events that regulate the prenylation and localization of small GTPases will help define new strategies for therapeutic targeting of these proteins in...
Identifying events that regulate the prenylation and localization of small GTPases will help define new strategies for therapeutic targeting of these proteins in disorders such as cancer, cardiovascular disease, and neurological deficits. Splice variants of the chaperone protein SmgGDS (encoded by RAP1GDS1) are known to regulate prenylation and trafficking of small GTPases. The SmgGDS-607 splice variant regulates prenylation by binding preprenylated small GTPases but the effects of SmgGDS binding to the small GTPase RAC1 versus the splice variant RAC1B are not well defined. Here we report unexpected differences in the prenylation and localization of RAC1 and RAC1B and their binding to SmgGDS. Compared to RAC1, RAC1B more stably associates with SmgGDS-607, is less prenylated, and accumulates more in the nucleus. We show that the small GTPase DIRAS1 inhibits binding of RAC1 and RAC1B to SmgGDS and reduces their prenylation. These results suggest that prenylation of RAC1 and RAC1B is facilitated by binding to SmgGDS-607 but the greater retention of RAC1B by SmgGDS-607 slows RAC1B prenylation. We show that inhibiting RAC1 prenylation by mutating the CAAX motif promotes RAC1 nuclear accumulation, suggesting that differences in prenylation contribute to the different nuclear localization of RAC1 versus RAC1B. Finally, we demonstrate RAC1 and RAC1B that cannot be prenylated bind GTP in cells, indicating that prenylation is not a prerequisite for activation. We report differential expression of RAC1 and RAC1B transcripts in tissues, consistent with these two splice variants having unique functions that might arise in part from their differences in prenylation and localization.
Topics: Protein Isoforms; Prenylation; Monomeric GTP-Binding Proteins; rac1 GTP-Binding Protein; Protein Prenylation
PubMed: 37059183
DOI: 10.1016/j.jbc.2023.104698 -
International Journal of Molecular... May 2022Protein prenylation is a post-translational modification controlling the localization, activity, and protein-protein interactions of small GTPases, including the Ras... (Review)
Review
Protein prenylation is a post-translational modification controlling the localization, activity, and protein-protein interactions of small GTPases, including the Ras superfamily. This covalent attachment of either a farnesyl (15 carbon) or a geranylgeranyl (20 carbon) isoprenoid group is catalyzed by four prenyltransferases, namely farnesyltransferase (FTase), geranylgeranyltransferase type I (GGTase-I), Rab geranylgeranyltransferase (GGTase-II), and recently discovered geranylgeranyltransferase type III (GGTase-III). Blocking small GTPase activity, namely inhibiting prenyltransferases, has been proposed as a potential disease treatment method. Inhibitors of prenyltransferase have resulted in substantial therapeutic benefits in various diseases, such as cancer, neurological disorders, and viral and parasitic infections. In this review, we overview the structure of FTase, GGTase-I, GGTase-II, and GGTase-III and summarize the current status of research on their inhibitors.
Topics: Carbon; Dimethylallyltranstransferase; Farnesyltranstransferase; Protein Prenylation; Terpenes
PubMed: 35628237
DOI: 10.3390/ijms23105424